Processes and intermediates in the synthesis of 5-(3-{exo-bicyclo{2.2.1}hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6- tetrahydropyrimidin-2(1H)-one

ABSTRACT

This invention relates to novel processes for preparing the pharmaceutically active compound 5-(3-[(2S)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2(1H)-one and its corresponding 2R enantiomer and for preparing certain intermediates used in the synthesis of these compounds. It also relates to novel intermediates used in the synthesis of such pharmaceutically active compounds and to other novel compounds that are related to such intermediates.

BACKGORUND OF THE INVENTION

[0001] This invention relates to novel processes for preparing thepharmaceutically active compound5-(3-[(2S)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2(1H)-oneand its corresponding 2R enantiomer and for preparing certainintermediates used in the synthesis of these compounds. It also relatesto novel intermediates used in the synthesis of such pharmaceuticallyactive compounds and to other novel compounds that are related to suchintermediates.

[0002] International Patent Application WO 87/06576, which was publishedon Nov. 5, 1987, refers to5-(3-[(2-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2(1H)-one,and states that it is useful as an antidepressant. International PatentApplication WO 91/07178, which was published on May 30, 1991, refers tothe utility of this compound in the treatment of asthma, inflammatoryairway diseases and skin diseases.

[0003] U.S. Pat. No. 5,270,206, which issued on Dec. 14, 1993, refers toa process for preparing (+)-(2R)-endo-norborneol (also referred to as(2R)-endo-bicyclo[2.2.1]heptan-2-ol or (1S, 2R,4R)-bicyclo[2.2.1]heptan-2-ol) and (−)-(2S)-endo-norborneol (alsoreferred to as (2S)-endo-bicyclo[2.2.1]heptan-2-ol or (1R, 2S,4S)-bicyclo[2.2.1]heptan-2-ol), and to their further conversion into thepharmaceutically active agents5-(3-[(2S)-exo-bicyclo[2.2.1)]hept-2-yloxy]4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2(1H)-one,depicted below,

[0004] and 5-(3-[(2R)-exo-bicyclo [2.2.1]hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2(1H)-one,depicted below,

[0005] All documents cited herein, including the foregoing, areincorporated herein by reference in their entireties.

SUMMARY OF THE INVENTION

[0006] This invention relates to a compound having the formula

[0007] wherein X and Y are the same and are selected from —CN,—CO₂(C₁-C₆)alkyl, —CONH₂ and —CONHOH, or X and Y, taken together, form agroup of the formula

[0008] This invention also relates to a compound having the formula

[0009] wherein R¹ and R² are independently selected from C(C₁-C₆) alkyland hydrogen.

[0010] This invention also relates to compounds of the formulae

[0011] wherein each R² is independently selected from (C₁-C₆) alkyl.

[0012] This invention also relates to a process for preparing a compoundof the formula

[0013] wherein X and Y are the same and are selected from —CN,—CO₂(C₁-C₆)alkyl, —CONH₂ and —CONHOH, or X and Y, taken together, form agroup of the formula

[0014] comprising: (1) reacting 3-hydroxy-4-methoxybenzaldehyde with acompound of the formula XCH₂CO₂H, wherein X is defined as above, in thepresence of a base, preferably a tertiary amine, to yield a compound ofthe formula II wherein X and Y are both —CN, —CO₂(C₁-C₆)alkyl, —CONH₂ or—CONHOH; or (2) (a) reacting a compound of the formula II wherein X andY are both —CN with hydrogen peroxide, preferably basic aqueous hydrogenperoxide, to form the corresponding bis-amide in which both —CN groupsare replaced by —CONH₂; (b) subjecting the bis-amide formed in step (a)to a Hoffman rearrangement using an oxidizing agent (e.g.,bis(acetoxy)iodobenzene, bis(trifluorocetoxy)iodobenzene, NaOCl, NaOBror lead tetraacetate) to form the corresponding biscarbamate; and (c)reacting the biscarbamate formed in step (b) with a base (e.g., analkali metal alkoxide containing from one to six carbon atoms or analkali metal hydroxide), to form a cyclic urea wherein X and Y, takentogether, form a group of the formula “a”, as depicted above.

[0015] This invention also relates to a process for preparing a compoundof the formula

[0016] wherein X and Y are defined as for formula II above, comprisingreacting a compound of formula II, as defined above, with, respectively,R-(+)-endo-norborneol or S-(−)-endo-norborneol, a triaryl or trialkylphosphine and an azo dicarboxylate.

[0017] This invention also relates to a process for preparing a compoundof the formula

[0018] wherein X and Y are the same and are selected from —CN, —CONH₂,CO₂(C₁-C₆)alkyl and —CONHOH, or X and Y, taken together, form a group ofthe formula

[0019] comprising: (1) reacting 3-hydroxy4-methoxybenzaldehyde with acompound of the formula XCH₂CO₂H, wherein X is —CN, —CO₂(C₁-C6)alkyl,—CONH₂ or —CONHOH, in the presence of a base, preferably a tertiaryamine, to form a compound of the formula

[0020] wherein X and Y are the same and are selected from —CN, —CONH₂,—CO (C₁-C₆)alkyl and —CONHOH; or (2) (a) reacting a compound of theformula II wherein X and Y are both —CN with hydrogen peroxide to formthe corresponding bis-amide in which both —CN groups are replaced by—CONH₂; (b) subjecting the bis-amide formed in step (a) to a Hoffmanrearrangement using an oxidizing agent (e.g., bis(acetoxy)iodobenzene,bis(trifluorocetoxy)iodobenzene, NaOCl, NaOBr or lead tetraacetate) toform the corresponding biscarbamate; and (c) reacting the biscarbamateformed in step (b) with a base (e.g., an alkali metal alkoxidecontaining from one to six carbon atoms), to form a cyclic area whereinX and Y, taken together, form a group of the formula

[0021] and then (3) reacting said compound of formula II so formed instep 1 or 2 above with, respectively, R-(+)-endo-norborneol orS-(−)-endo-norborneol, a triaryl or trialkyl phosphine and an azodicarboxylate.

[0022] This invention also relates to a process for preparing a compoundof the formula

[0023] wherein R¹ and R² are independently selected from hydrogen and(C₁-C₆)alkyl, comprising reacting, respectively, a compound of theformula

[0024] with diacetoxyiodobenzene, NaOZ and Z′OH, wherein Z and Z′ areindependently selected from hydrogen and (C₁-C₆)alkyl.

[0025] This invention also relates to a process for preparing a compoundof the formula

[0026] comprising reacting, respectively, a compound of the formula

[0027] wherein R¹ and R² are independently selected from hydrogen and(C₁-C₆)alkyl with compounds of the formulae NaOZ and Z′OH, wherein Z andZ′ are independently selected from hydrogen and (C₁-C₆)alkyl.

[0028] This invention also relates to a process for preparing a compoundof the formula

[0029] comprising:

[0030] reacting, respectively, a compound of the formula

[0031] with diacetoxyiodobenzene, NaOZ and Z′OH, wherein Z and Z′ areindependently selected from hydrogen and (C₁-C₆)alkyl, to form anintermediate of the formula

[0032] wherein R¹ and R² are independently selected from hydrogen and(C₁-C₆)alkyl; and then either

[0033] (b1) isolating said intermediate of formula V or V′ and reactingit with compounds of the formulae NaOZ and Z′OH, wherein Z and Z′ aredefined as above; or

[0034] (b2) reacting said intermediate of formula V or V′ in situ withcompounds of the formula NaOZ and Z′OH, wherein Z and Z′ are defined asabove.

[0035] As used herein, the expression “reaction inert solvent” refers toa solvent which does not interact with starting materials, reagents,intermediates or products in a manner which adversely affects the yieldof the desired product or products.

[0036] The term “alkyl”, as used herein, unless otherwise indicated,includes saturated monovalent hydrocarbon radicals having straight,branched or cyclic moieties or combinations thereof.

[0037] Formulae II, and V and V′ above include compounds identical tothose depicted but for the fact that one or more hydrogen, carbon,nitrogen or oxygen atoms are replaced by radioactive or stable isotopesthereof. Such radiolabelled compounds are useful as research anddiagnostic tools in metabolism pharmacokinetic studies and in bindingassays.

DETAILED DESCRIPTION OF THE IVNENTION

[0038] The processes of the this invention and methods of preparing thenovel compounds of this invention are described in the followingreaction schemes and discussion. Unless otherwise indicated, thesubstituents X, Y, R, R¹, R², R³, and R⁴, group “(a)” and formulae II,III, III′, IV, IV′, V, V′, VI and VI′ in the reaction schemes anddiscussion that follow are defined as above.

[0039] Scheme 1 illustrates the preparation of compounds of the formulaeII and III. Scheme 2 illustrates the preparation of compounds of theformula V and also the preparation of5-(3-[(2S)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2-(1H)-one(compound VI) from the compound of formula III wherein X and Y are both—CN. (Such compound of formula III wherein X and Y are both —CN isreferred to in scheme 2 and hereinafter as the compound of formulaIIIA.) Scheme 3 illustrates the preparation of compound VI fromcompounds of the formula III wherein X and Y are both —CO₂(C₁-C₆)alkylor —CONHOH. (The compound of formula III wherein X and Y are both—CO₂(C₁-C₆)alkyl or —CONHOH are referred to in scheme 3 and hereinafter,respectively, as the compound of formula IIIB or IIIC).

[0040] Referring to scheme 1, isovanillin (compound I) is condensed withtwo molar equivalents of a compound of the formula XCH₂CO₂H, wherein Xis —CN, —CO₂(C₁-C₆)alkyl, —CONH₂ or —CONHOH, in a sequentialKnoevenagel-Michael sense with accompanying decarboxylation, to yield acompound of the formula II, wherein X and Y are the same and areselected from the values given in the above definition of X, in areaction inert solvent in the presence of a base, preferably a tertiaryamine. This reaction may be conducted at a temperature ranging fromabout 10° C. to about 130° C. It is preferably conducted at about thereflux temperature. Suitable solvents include but are not limited toN-methylmorpholine, triethylamine, pyridine, as well as non-basicreaction-inert solvents such as tetrahydrofuran (THF), dimethylformamide(DMF), acetonitrile and toluene. Preferably, a secondary amine (e.g.,piperidine or pyrrolidine) is also added as a catalyst. In one preferredembodiment of the reaction, N-methylmorpholine is used as thesolvent/base and piperidine is also added to the reaction mixture.

[0041] Compounds of the formula II wherein X and Y, taken together, forma group of the “a” (i.e., the cyclic urea) may be prepared by subjectingthe compound of formula II wherein X and Y are both —CN to the series ofreactions illustrated in scheme 2 and described later in thisapplication.

[0042] The compound of formula II formed in the above reaction can beconverted into the corresponding compound of the formula III by couplingit under Mitsunobu conditions with either R-(+)-endo-norborneol,depicted below,

[0043] or S-endo-norborneol, depicted below

[0044] to yield, respectively, the corresponding compound of formula IIIor III′ having the opposite stereochemistry as determined by theendo-norborneol reactant. Thus, if R-endo-norborneol is used, theproduct will be a compound of the formula III that has an “S”configuration, and if S-endo-norborneol is used, the product will be acompound of the formula III′ that has an “R” configuration.

[0045] This reaction is typically carried out in the presence of atriaryl or trialkyl phosphine such as triphenylphosphine ortributylphosphine and an azo dicarboxylate oxidizing agent. It is alsogenerally carried out in an aprotic solvent such as tetrahydrofuran(THF) acetonitrile, methylene chloride, DMF, toluene and benzene,preferably THF, at atemperature from about 10° C. to about 150° C.,preferably at about the reflux temperature. Suitable azo compoundsinclude diisopropylazodicarboxylate, azodicarbonyldipiperidine anddiethylazodicarboxylate. Diisopropylazodicarboxylate andazodicarbonyldipiperidine are preferred.

[0046] The stereochemistry of the compound of formula III or III′ formedin the above step is retained in all subsequent steps shown in schemes 2and 3.

[0047] As indicated above, scheme 2 illustrates the conversion ofcompounds of the formula IIIA into compounds of the formula VI.Referring to scheme 2, a compound of the formula IIIA is hydrolyzed withhydrogen peroxide, preferably basic aqueous hydrogen peroxide, to formthe bis-amide of formula IV. This reaction is typically conducted in apolar solvent such as acetone, ethanol, isopropanol or methyl ethylketone, with acetone being preferred, at atemperature from about 0° C.to about 100° C., with about room temperature being preferred. Sodiumcarbonate or another inorganic salt of similar basicity may be added tothe reaction mixture to accelerate the reaction.

[0048] The compound of formula IV so formed is then subjected to aHoffman rearrangement reaction in which both carboxamide groups areconverted, with migration of nitrogen, into the carbamate groups offormula V. Suitable oxidizing reagents include bis(acetoxy)iodobenzene,bis(trifluoroacetoxy)iodobenzene, NaOCl, NaOBr and lead tetracetate maybe used. Bis(acetoxy)iodobenzene is preferred. This reaction istypically carried out in the presence of a base. Whendiacetoxyiodobenzene is used, acceptable bases include alkali metalhydroxides and (C₁-C₆)alkoxides. The reaction temperature may range fromabout −20° C. to about 100° C., with from about 0° C. to about 25° C.being preferred. Examples of appropriate reaction-inert solvents are(C-C₆)alkanols, THF, DMF and acetonitrile.

[0049] The final step in the sequence is the base catalyzed closure ofthe biscarbamate of formula V to form the symmetrical pyrimidin-2-one offormula VI. This reaction may be carried out from about 0° C. to about100° C., and is preferably carried out at the reflux temperature.Suitable solvents include but are not limited to lower alcohols, withmethanol being preferred. Suitable bases include alkali metal alkoxidescontaining from one to six carbon atoms. The preferred base is sodiummethoxide.

[0050] Alternatively, the last two steps of the sequence may beaccomplished in a combined fashion without the isolation of thebis-carbamate V. This modification is essentially identical to theprevious description of the Hoffman rearrangement. It is preferable toconduct the reaction at the reflux temperature of the solvent. It isalso preferable to add additional base to the reaction mixture. Therange of acceptable oxidizing agents, bases and solvents is the same asdescribed previously. The preferred reaction utilizesdiacetoxyiodobenzene, sodium methoxide and methanol.

[0051] The reaction of compounds of the formula V to form compounds ofthe formula VI, as described above, may proceed through one or both ofthe intermediates of formulae VII and VII shown in scheme 2A.

[0052] The compound of formula III wherein X and Y are both —CONH₂ isthe same as the compound of formula IV, and therefore it can beconverted into compound (VI) using the methods illustrated in scheme 2.

[0053] Compounds of the formula III wherein X and Y are both —CONHOH or—CO₂(C₁-C₆)alkyl may be converted into compound VI using the methodsillustrated in scheme 3.

[0054] Referring to scheme 3, the diester of formula IIIB is reactedwith hydroxylamine hydrochloride in the presence of a base, e.g., atertiary amine base, to form the hydroxamic acid of formula IIIC. Thisreaction can be conducted in a variety of reaction-inert solvents thatdo not have a strong nucleophilic character, including but not limitedto lower alcohols, cyclic and acyclic ethers (e.g., ethyl ether or THF),neutral aromatic compounds such as benzene and toluene, DMF,dimethylacetamide, ethyl acetate, acetonitrile and water, at atemperature from about 0° C. to about 100° C., preferably at about 20°C.

[0055] The hydroxamic acid of formula IIIC can then be converted intocompound VI via a Loessen rearrangement using conditions or a reagenthaving the ability to dehydrate an alcohol, at a temperature from about0° C. to about 100° C., preferably at about 20° C. The preferred reagentis p-toluenesulfonylchloride. Alternatively, one can form a differentester of the hydroxamic acid, optionally in situ, and then convert thatester via heat and/or acid treatment into the compound of formula VI,using methods well known in the art.

[0056] The preparation of other compounds of the present invention notspecifically described in the foregoing experimental section can beaccomplished using combinations of the reactions described above thatwill be apparent to those skilled in the art.

[0057] In each of the reactions discussed or illustrated in the schemeabove, pressure is not critical unless otherwise indicated. Pressuresfrom about 0.5 atmospheres to about 3 atmospheres are generallyacceptable, and ambient pressure, i.e., about 1 atmosphere, is preferredas a matter of convenience.

[0058] The processes and products of this invention are useful in thesynthesis of the pharmaceutically active compounds VI and VI′. CompoundsVI and VI′, as well as racemic mixtures of these compounds (hereinafterreferred to, collectively as “the active compounds”) are useful in thetreatment of depression, asthma, inflammatory airway disorders and skindisorders (e.g., psoriasis and atopic dermatitis).

[0059] The active compounds are calcium independent c-AMPphosphodiesterase inhibitors. The ability of such compounds to inhibitc-AMP phosphodiesterase may be determined by the method of Davis,Biochimica et Biophysica. Acta., 797, 354-362 (1984).

[0060] The antidepressant activity of the active compounds may bedetermined by the behavioral despair paradigm described by Porsult etal., Arch. Int. Pharmacodyn., 227, 327-336 (1977) and by the proceduredescribed by Roe et al., J. Pharmacol. Exp. Therap., 226, 686-700 (1983)for determining the ability of a test drug to counteract reserpinehypothermia in mice.

[0061] When used for the treatment of depression the active compoundsare used as is or in the form of pharmaceutical compositions comprisingan active compound and pharmaceutically-acceptable carriers or diluents.For oral administration, the preferred route for administering theactive compounds, suitable pharmaceutical carriers include inertdiluents or fillers, thereby forming dosage forms such as tablets,powders, capsules, and the like. These pharmaceutical compositions can,if desired, contain additional ingredients such as flavorings, binders,excipients and the like. For example, tablets containing variousexcipients, such as sodium citrate, are employed, together with variousdisintegrants such as starch, alginic acid and certain complexsilicates, together with binding agents such as polyvinylpyrrolidone,sucrose, gelatin and acacia. Additionally, lubricating agents such asmagnesium stearate, sodium lauryl sulfate and talc are often useful fortabletting purposes. Solid compositions of a similar type may also beemployed as fillers in soft and hard filled gelatin capsules. preferredmaterials therefor include lactose or milk sugar and high molecularweight polyethylene glycols.

[0062] For oral administration, the daily dose of active agent is fromabout 0.1 mg to about 10 mg, and for parenteral administration,preferably i.v. or i.m., from about 0.01 mg. to about 5 mg. Theprescribing physician, of course, will ultimately determine theappropriate dose for a given human subject dependent upon factors suchas the severity of the patient's symptoms and the patient's response tothe particular drug.

[0063] In vitro and in vivo tests relevant to the utility of the activecompounds in treating asthma and skin disorders are discussed inInternational Patent Application WO 91/07178, referred to above andincorporated herein by reference in its entirety, on pages 4 and 5 ofthe specification and in Examples 1-3.

[0064] In the systemic treatment of asthma or inflammatory skin diseaseswith one of the active compounds, the dosage is generally from about0.01 to 2 mg/kg/day (0.5-100 mg/day in a typical human weighing 50 kg)in single or divided doses, regardless of the route of administration.Of course, depending upon the exact compound and the exact nature of theindividual illness, doses outside this range will be prescribed at thediscretion of the attending physician. In the treatment of asthma,intranasal (drops or spray), inhalation of an aerosol through the mouth,and conventional oral administration are generally preferred. However,if the patient is unable to swallow, or oral absorption is otherwiseimpaired, the preferred systemic route of administration will beparenteral (i.m., i.v.). In the treatment of inflammatory skin diseases,the preferred route of administration is oral or topical. In thetreatment of inflammatory airway diseases, the preferred route ofadministration is intranasal or oral.

[0065] The active compounds are generally administered in the form ofpharmaceutical compositions comprising one of said compounds togetherwith a pharmaceutically acceptable vehicle or diluent. Such compositionsare generally formulated in a conventional manner utilizing solid orliquid vehicles or diluents as appropriate to the mode of desiredadministration: for oral administration, in the form of tablets, hard orsoft gelatin capsules, suspensions, granules, powders and the like; forparenteral administration, in the form of injectable solutions orsuspensions, and the like; for topical administration, in the form ofsolutions, lotions, ointments, salves and the like, in generalcontaining from about 0.1 to 1% (w/v) of the active ingredient; and forintranasal or inhaler administration, generally as 0.1 to 1% (w/v)solution.

[0066] The present invention is illustrated by the following examples.It will be understood, however, that the invention is not limited to thespecific details of these examples.

EXAMPLE 1 3-(3-Hydroxy4-methoxyphenyl)-pentane-1,5-dinitrile

[0067] To a 500 mL flask containing isovanillin (30.4 gm, 200 mmol) andcyanoacetic acid (68.0 gm, 800 mmol) was charged a solution consistingof 3.0 mL (30 mmol) piperidine and 151 mL N-methylmorpholine. Theinitially formed yellow slurry was warmed to mild reflux for 21 hoursand then cooled to room temperature and concentrated on a rotaryevaporator. The resulting brown oil was dissolved in 430 mL ethylacetate (EtOAc), washed sequentially with water (H₂O), five normalhydrochloric acid (5N HCl) and H₂O and the combined aqueous washes backextracted with dichloroethane. Combination of the organic layersfollowed by solvent removal led to thick orange oil which wascrystallized from ethyl acetate/methylene chloride EtOAc/CH₂Cl₂) toyield 38.3 gm of orange solids after filtration and drying.Recrystallization from EtOAc/diisopropyl ether gave 35.3 gm (82%) oflight yellow solid, m.p. 90-92° C.

EXAMPLE 23-(3-[(2S)-exo-Bicyclo[2.2.1]hept-2-yloxy]-4-methoxvphenvl)-1,5-pentanedinitrile

[0068] To a tetrahydrofuran (THF) solution (20 mL) containingR-(+)-endo-norborneol (1.12 gm, 10.0 mmol),3-(3-hydroxy-4-methoxyphenyl)-pentane-1,5-dinitrile (4.33 gm, 20 mmol)and triphenylphosphine (TPP) (3.93 gm, 15 mmol) was added1,1′-(azodicarbonyl)-dipiperidine (ADDP) (3.78 gm, 15 mmol) at roomtemperature. The resulting brown slurry was heated at reflux for 12hours, and then diluted with 10 mL THF and 30 mL toluene, cooled to roomtemperature and granulated for 30 minutes. After filtration to removethe reduced ADDP, the filtrate was washed 2× with 20 ml 1 N sodiumhydroxide (NaOH) and the remaining organic phase stirred with 0.2 gmactivated charcoal and 20 gm sodium sulfate (Na₂SO₄), filtered andconcentrated to a thick, dark brown oil. Recrystallization fromisopropanol/hexanes gave 2.34 gm (75%) of an off-white solid, m.p.126-127° C.

EXAMPLE 33-(3-[(2S)exo-Bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-pentane-1,5-dinitrile

[0069] To a refluxing solution of THF (30 mL) containing norborneol(2.243 gm, 20.00 mmol) and triphenylphosphine (5.272 gm, 20.10 mmol) wasadded a second THF solution of3-(3-hydroxy4-methoxyphenyl)-pentane-1,5-dinitrile (4.350 gm, 20.10mmol) and diisopropyl azodicarboxylate (DIAD) (4.044 gm, 21.00 mmol).The mixture was heated at reflux for 18 hours, cooled and concentratedon the rotary evaporator, and then redissolved in 60 mL toluene. Theresulting brown toluene solution was washed 2 times with 1 N NaOH, driedover Na₂SO₄, and filtered and concentrated to yield 18 gm of beigesolid. Recrystallization from 1/1 isopropanol/hexanes gave 4.26 gm (69%)of white solid, m.p. 127-128° C.

EXAMPLE 43-(3-[(2S)-exo-Bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)glutaramide

[0070] To a cooled (6° C.) acetone solution (46 mL) of3-(3-[(2S)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-pentane-1,5-dinitrile (2.29 gm,7.38 mmol) was added 24 mL of 10% aqueous sodium carbonate (Na₂CO₃) (23mmol) followed by 5.2 mL of 30% hydrogen pyroxide (H₂O₂). The resultingslurry was stirred at room temperature for 4 days, treated with anadditional 1.7 mL 30% H₂O₂ and then stirred for two more days. Theexcess peroxide was decomposed by the addition of 4 equivalents ofsodium bisulfite (NaHSO₃) and the volume was reduced to about 80 mL onthe rotary evaporator. The thick slurry was then acidified using 6.5 mLof concentrated HCl, neutralized with concentrated ammonium hydroxide(NH₄OH) and condensed to about 50 mL of volume. Filtration and vacuumdrying provided 2.20 gm (86%) of white solids, m.p. 161-163° C.

EXAMPLE 55-(3-[(2S)-exo-Bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6-tetrahydropyrinidin-2(1H)-one

[0071] To a cooled (2°) methanol (MeOH) (40 mL) suspension ofdiacetoxyiodobenzene (43.60 gm, 133 mmol) was added 152 mL of 25% sodiummethoxide (NaOMe) in MeOH solution over 10 minutes. After stirring for20 minutes at 3° C., 3-(3-[(2S)-exo-bicyclo[2.2.1]hept-2-yloxy]4-methoxyphenyl)glutaramide (22.98 gm, 66.5 mmol) was addedas a precooled slurry in 45 mL MeOH and the reaction was allowed to warmto room temperature over 3 hours followed by 45 minutes of heating atreflux. The slurry was cooled to room temperature, treated with 152 mLof 25% NaOMe in MeOH solution and heated to reflux for 16 hours. Thecondenser was then replaced with a distillation head and 350 mL of MeOHwas removed. The resulting slurry was cooled to 12° C., diluted with 200mL CH₂Cl₂ and 100 ml H₂O and neutralized with concentrated HCl.Separation of the layers and extraction of the aqueous layer 2× withCH₂Cl₂ provided 3 organic layers which were combined, dried over sodiumsulfate (Na₂SO₄), filtered and then concentrated to yield 39 gm of paleorange solid. Reslurry in refluxing EtOAc gave 15.48 gm of white solid(77%) m.p. 199-200° C.

EXAMPLE 6N,N′-Dimethoxycarbonyl-2-(3-[(2S)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-1,3-propanediamine

[0072] To a cooled (0° C.) suspension of3-(3-[(2S)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-glutaramide(0.346 gm, 1.00 mmol) in 1.75 ml of MeOH was added 0.140 gm of potassiumhydroxide (KOH) (2.50 mmol) followed by 0.657 gm (3.0 mmol)diacetoxyiodobenzene. The resulting hazy yellow solution was allowed towarm to room temperature, stir for 80 minutes and was then concentratedon the rotary evaporator to a paste. The material was transferred to aseparatory funnel with water and extracted two times with CH₂Cl₂. Thecombined organic layers dried over Na₂SO₄, filtered and concentrated toprovide 0.506 gm (125%) of the desired bis-carbamate as an impure yellowfoam. Thin layer chromatography (TLC): R_(f)=0.74 in 9:1 CH₂Cl₂/MeOH.Gas chromatography—mass spectrometry showed the major peak with amolecular ion of 406 which is the molecular weight of the titlecompound.

EXAMPLE 75-(3[(2R)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2(1H)-one

[0073] The crude bis-carbamate foam from Example 6 (98 mg, 0.2 mmol) wasdissolved in MeOH (0.5 mL), treated with 0.5 mL of 25% NaOMe in MeOH,and refluxed for 18 hours. After removal of the solvent, the resultingsolid was dissolved in water, extracted two times with CH₂Cl₂ and thecombined organic layers dried over magnesium sulfate (MgSO₄). Filtrationand concentration of the filtrate gave 48 mg (75%) of the desired ureaas a yellow solid. Thin layer chromatography (TLC): R_(f)=0.57 in 9:1CH₂Cl₂/MeOH.

1. A process for preparing a compound of the formula

comprising: (a) reacting, respectively, a compound of the formula

with diacetoxyiodobenzene, NaOZ and Z′OH, wherein Z and Z′ areindependently selected from hydrogen and (C₁-C₆)alkyl, to form anintermediate of the formula

wherein R¹ and R² are independently selected from hydrogen and(C₁-C₆)alkyl; and then either: (b1) isolating said intermediate offormula V or V′ and reacting it with compounds of the formulae NaOZ andZ′OH, wherein Z and Z′ are defined as above; or (b2) reacting saidintermediate of formula V or V′ in situ with compounds of the formulaNaOZ and Z′OH, wherein Z and Z′ are defined as above.
 2. A process forpreparing a compound of the formula

wherein X and Y are the same and are selected from —CN₁, —CONH₂,—CO₂(C₁-C₆)alkyl and —CONHOH, or X and Y, taken together, form a groupof the formula

comprising: (1) reacting 3-hydroxy-4-methoxybenzaldehyde with a compoundof the formula XCH₂CO₂H, wherein X is —CN, —CO₂(C₁-C₆)alkyl, —CONH₂ or—CONHOH, in the presence of a base, to form a compound of the formula

wherein X and Y are the same and are selected from —CN, —CONH₂,—CO₂(C₁-C₆)alkyl and —CONHOH; or (2) (a) reacting a compound of theformula II wherein X and Y are both —CN with hydrogen peroxide to formthe corresponding bis-amide in which both —CN groups are replaced by—CONH₂; (b) subjecting the bis-amide formed in step (a) to a Hoffmanrearrangement using an oxidizing agent to form the correspondingbiscarbamate; and (c) reacting the biscarbamate formed in step (b) witha base to form a cyclic area wherein X and Y, taken together, form agroup of the formula

and then (3) reacting said compound of formula II formed in step 1 or 2above with a triaryl ortrialkylphosphine, an azo dicarboxylate, andeither R-(+)-endo-norborneol or S-(−)-endo-norborneol, respectively. 3.A process according to claim 2 wherein said base is a tertiary amine. 4.A process according to claim 2 wherein both a tertiary amine and asecondary amine are added to the reaction mixture.
 5. A processaccording to claim 4 wherein the tertiary amine is selected fromN-methylmorpholine, triethylamine, pyridine and diisopropyl amine andthe secondary amine is selected from piperidine and pyrrolidine.
 6. Aprocess according to claim 2 wherein the azo dicarboxylate is selectedfrom diisopropylazadicarboxylate and azodicarbonyldipiperidine.
 7. Aprocess according to claim 2 wherein the triarylphosphine istriphenylphosphine.
 8. A process for preparing a compound of the formula

comprising reacting, respectively, a compound of the formula

wherein R¹ and R² are independently selected from hydrogen and(C₁-C₆)alkyl, with compounds of the formulae NaOZ and Z′OH, wherein Zand Z′ are independently selected from hydrogen and (C₁-C₆)alkyl.
 9. Acompound having the formula

wherein X an Y are the same and are selected from —CO₂(C₁-C₆)alkyl,—CONH₂ and —CONHOH, or X and Y, taken together, form a group of theformula


10. A compound according to claim 9 wherein X and Y are both —CONH₂. 11.A compound according to claim 9 wherein X and Y, taken together, form agroup of the formula


12. A compound according to claim 9 wherein X and Y are both—CO₂(C₁-C₆)alkyl.
 13. A compound according to claim 9 wherein X and Yare both —CONHOH.
 14. A compound having the formula

wherein R¹ and R² are independently selected from (C₁-C₆)alkyl andhydrogen.
 15. A compound according to claim 14 wherein both R¹ and R²are selected from (C₁-C₆)alkyl.
 16. A compound according to claim 14wherein both R¹ and R² are hydrogen.
 17. A process for preparing acompound of the formula

wherein X and Y are the same and are selected from —CO₂(C₁-C₆)alkyl,—CONH₂ and —CONHOH, or X and Y, taken together, form a group of theformula

comprising: (1) reacting 3-hydroxy4-methoxybenzaldehyde with a compoundof the formula XCH₂CO₂H, wherein X is selected from —CO₂(C₁-C₆)alkyl,—CONH₂ and —CONHOH, in the presence of a base, to yield a compound ofthe formula II wherein X and Y are both —CO₂(C₁-C₆)alkyl, —CONH₂ or—CONHOH; or (2) (a) reacting a compound of the formula II wherein X andY are both —CN with hydrogen peroxide to form the correspondingbis-amide in which both —CN groups are replaced by —CONH₂; (b)subjecting the bis-amide formed in step (a) to a Hoffman rearrangementusing an oxidizing agent to form the corresponding biscarbamate; and (c)reacting the biscarbamate formed in step (b) with a base to form acyclic urea wherein X and Y, taken together, form a group of the formula


18. A process according to claim 17 , wherein3-hydroxy-4-methoxybenzaldehyde is reacted with HOOCCH₂CONHOH.
 19. Aprocess according to claim 17 , wherein 3-hydroxy-4-methoxybenzaldehydeis reacted with HOOCCH₂CONH₂.
 20. A process according to claim 17 ,wherein 3-hydroxy-4-methoxybenzaldehyde is reacted withHOOCCCH₂CO₂(C₁-C₆)alkyl.
 21. A process according to claim 17 , whereinsaid base is a tertiary amine.
 22. A process according to claim 17 ,wherein both a tertiary amine and a secondary amine are added to thereaction mixture.
 23. A process according to claim 22 , wherein saidsecondary amine is piperidine or pyrrolidine.
 24. A process forpreparing a compound of the formula

wherein X and Y are the same and are selected from —CN₁—CONH₂,CO₂(C₁-C₆)alkyl and —CONHOH, or X and Y, taken together, form a group ofthe formula

comprising reacting a compound of the formula

wherein X and Y are the same and are defined as above, with a triaryl ortrialkylphosphine, an azo dicarboxylate and either R(+)-endo-norborneolor S-(−)-endo-norborneol, respectively.
 25. A process for preparing acompound of the formula

wherein R¹ and R² are independently selected from hydrogen and(C₁-C₆)alkyl, comprising reacting, respectively, a compound of theformula

with diacetoxyiodobenzene, NaOZ and Z′OH, wherein Z and Z′ areindependently selected from hydrogen and (C₁-C₆)alkyl.
 26. A processaccording to claim 25 , further comprising reacting said compound offormula V or V′ with compounds of the formulae ZONa and Z′OH, wherein Zand Z′ are defined as in claim 25 , to yield, respectively, a compoundof the formula


27. A compound of the formula

wherein each R² is independently selected from (C₁-C₆)alkyl.